title: The tumor suppressor activity of IKKalpha in stratified epithelia is exerted in part via the TGF-beta antiproliferative pathway.
abstract: The transforming growth factor type beta-1 (TGF-beta) signaling pathway is a major tumor suppressor during early carcinogenesis, and its growth-suppressive activity is commonly lost during early tumor progression. IkappaB kinase alpha (IKKalpha) also acts as a tumor suppressor in stratified epithelia, and its expression and nuclear localization are progressively down-regulated during malignant progression of squamous cell carcinoma (SCC) and acquisition of an invasive phenotype. A critical role for IKKalpha in TGF-beta signaling in stratified epithelia was identified recently during normal keratinocyte differentiation, and both IKKalpha and components of the TGF-beta signaling pathway are required for induction of antiproliferative Myc antagonists in such cells. We now describe that the interaction between IKKalpha and the TGF-beta signaling pathway is also important in a subset of SCCs. In SCCs that are unable to shuttle IKKalpha to the nucleus, defective TGF-beta-induced growth arrest was rescued by introduction of a constitutively nuclear IKKalpha variant. These results suggest that the tumor-suppressive activity of IKKalpha in stratified epithelia may be exerted in part via the TGF-beta signaling pathway.
authors.affiliation: Departments of Dermatology and Gastroenterology, University of Rome "Tor Vergata", 00133 Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Marinari
authors.forename: Francesca
authors.initials: F
authors.lastname: Moretti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Botti
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Giustizieri
authors.forename: Pascal
authors.initials: P
authors.lastname: Descargues
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giunta
authors.forename: Carmine
authors.initials: C
authors.lastname: Stolfi
authors.forename: Costanza
authors.initials: C
authors.lastname: Ballaro
authors.forename: Marina
authors.initials: M
authors.lastname: Papoutsaki
authors.forename: Stefano
authors.initials: S
authors.lastname: Alemà
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
authors.forename: Sergio
authors.initials: S
authors.lastname: Chimenti
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Antonio
authors.initials: A
authors.lastname: Costanzo
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell; D049109:Cell Proliferation; D015536:Down-Regulation; D004848:Epithelium / Q000201:enzymology / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D051550:I-kappa B Kinase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D016271:Proto-Oncogene Proteins c-myc; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D016212:Transforming Growth Factor beta; D051550:I-kappa B Kinase